The 42 kDa processed fragment of the Plasmodium falciparum Merozoite Surface Protein 1, MSP1-42, is a leading protective human malaria vaccine currently undergoing clinical studies. Protective immunity is antibody-mediated, and directed to the C-terminal, immunodominant 19 kDa region of MSP1-42, or MSP1-19. Available evidence indicates that the vaccine-induced immunity to MSP1-42 or MSP-19 relies on the use of very powerful adjuvants (i.e. CFA) and on repeated hyper-immunizations to elicit high levels of protective antibodies. These are formidable obstacles in the way of field deployment of the malaria vaccine. Recently, we have shown that by refocusing the antibody responses to the N-terminal immuno-silent region of MSP1-42, MSP1-33, biologically active antibodies can be produced when combined with low concentrations of anti-MSP1-42 antibodies. This creates an opportunity to devise new vaccine constructs and/or immunization regimens to efficiently induce protective antibodies under the more favorable logistics of a reduced immunization schedule and the use of readily acceptable adjuvants. Accordingly, Specific Aim 1 will explore strategies to develop bivalent MSP1 vaccines as well as prime/boost immunization regimens, based on MSP1-33 and MSP1-42, in order to achieve a balanced induction of protective antibody responses. The focus will be on the use of less powerful adjuvants and a reduced immunization schedule. Specific Aim 2 will define experimental conditions in which combinations of anti-MSP1-33 and anti-MSP1-42 antibodies will inhibit parasites carrying different allelic and variant forms of MSP-42. This information, together with the down-selected vaccination strategies from Specific Aim 1, will be used to formulate MSP1-33/MSP1-42 vaccines to elicit strain-transcending, parasite inhibitory antibody responses. Significance: This exploratory project provides the critical proof-of- principle on which further development and validation of the dual MSP1-33/MSP1-42 vaccine strategy can be based. The strategy will rapidly lead to a new generation of MSP1-based malaria vaccines deployable with significantly improved efficacy and logistical feasibility, while utilizing the already existing technologies/platforms of demonstrated safety. [unreadable] [unreadable] PUBLIC HEALTH RELEVANCE - PROJECT NARRATIVE: Malaria is a major killer in developing countries and the development of effective vaccines is critical in controlling this deadly disease. This exploratory application seeks to improve the efficacy and the logistical feasibility of deployment of a leading candidate human malaria vaccine, Merozoite Surface Protein 1, MSP1. This is based on new and significant discovery of the immune responses to the MSP1 vaccine, which allows for novel re-design of the vaccine. Success in this project will move this vaccine forward in terms of significantly improving its potential to be effective in large populations in the field. [unreadable] [unreadable] [unreadable]